Medicines for cardiac insufficiency

Abstract

PCT No. PCT/JP94/00544 Sec. 371 Date Sep. 29, 1995 Sec. 102(e) Date Sep. 29, 1995 PCT Filed Apr. 1, 1994 PCT Pub. No. WO94/22442 PCT Pub. Date Oct. 13, 1994Disclosed are cardiotonic medicines containing, as the active ingredient, at least one of compounds of formula (I) and their pharmacologically acceptable salts when they form salts. wherein X1 and X2 do not exist or represents an oxygen atom; A represents OH or a C1-C4 acyloxy group; B represents a hydrogen atom or may form a chemical bond along with A; X is an oxygen atom, nitrogen, sulfur, etc.; R1 and R2 each represents a hydrogen atom, a C1-C4 alkyl group, etc.; R3 and R4 each represents a hydrogen atom, a C1-C4 alkyl group, etc., or they may together form a 1,4-butylene or 1,5-pentylene group. The compounds have a strong activity of reinforcing the contraction of cardiac muscles and a strong activity of reducing the rate of heart beats. As they are not toxic, they are useful as cardiotonic medicines.

We claim: 
     
       1. A method for treating cardiac insufficiency comprising administering an effective dose of, as an active ingredient, at least one compound of the following formula (I), their optical isomers, their stereoisomers and their pharmacologically acceptable salts when they may form salts: ##STR76## wherein X 1  and X 2  do not exist or represent an oxygen atom; X represents an oxygen atom; a sulfur atom; a nitrogen atom, said nitrogen atom is unsubstituted or substituted by a hydrogen atom or a C 1  -C 4  alkyl group; C(O); C(S); or C(N--CN); A represents a hydrogen atom; a hydroxyl group; or OC(O)R 5  wherein R 5  represents a C 1  -C 4  alkyl group; or may form a single bond together with B;   B represents a hydrogen atom, or may form a single bond together with A;   R 1  and R 2  are the same or different from each other and represent a hydrogen atom or a C 1  -C 4  alkyl group, or R 1  and R 2  may together form a 1,4-butylene or 1,5-pentylene group which is unsubstituted or substituted by a C 1  -C 4  alkyl group;   R 3  and R 4  are the same or different from each other and represent: 1) a hydrogen atom;   2) a C 1  -C 6  alkyl group, said alkyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom; a carboxyl group; a C 2  -C 5  alkoxy carbonyl group; a hydroxyl group; a C 1  -C 4  alkoxy group; CH(OR) 2  in which R represents a C 1  -C 4  alkyl group; a phenyl group which is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group and a C 1  -C 4  alkoxy group; a formyl group; a cyano group and a nitro group;   3) a C 2  -C 6  alkenyl group, said alkenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom; a carboxyl group; a C 2  -C 5  alkoxycarbonyl group; a hydroxyl group; a C 1  -C 4  alkoxy group; CH(OR) 2  in which R represents a C 1  -C 4  alkyl group; a phenyl group which is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, and a C 1  -C 4  alkoxy group, a formyl group; a cyano group and a nitro group;   4) a C 2  -C 6  alkynyl group, said alkynyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom; a carboxyl group; a C 2  -C 5  alkoxycarbonyl group; a hydroxyl group; a C 1  -C 4  alkoxy group; CH(OR) 2  in which R represents a C 1  -C 4  alkyl group; a phenyl group which is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group and a C 1  -C 4  alkoxy group; a formyl group; a cyano group and a nitro group;   5) a C 2  -C 6  cycloalkyl group, said cycloalkyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom; a carboxyl group; a C 2  -C 5  alkoxycarbonyl group; a hydroxyl group; a C 1  -C 4  alkoxy group; CH(OR) 2  in which R represents a C 1  -C 4  alkyl group; a phenyl group which is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group and a C 1  -C 4  alkoxy group; a formyl group; a cyano group and a nitro group;   6) a phenyl group which is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group and a C 1  -C 4  alkoxy group; or     R 3  and R 4  may together form a 1,4-butylene or 1,5-pentylene group, said 1,4-butylene group and 1,5-pentylene group are unsubstituted or substituted by one or more substituents selected from a C 1  -C 4  alkyl group; a phenyl group which is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group and a C 1  -C 4  alkoxy group; a halogen atom; OR 10  in which R 10  represents a hydrogen atom, a C 1  -C 4  alkyl group; COR 11  wherein R 11  represents a C 1  -C 4  alkyl group; a nitro group; SO 3  H or PO 3  H 2  ; or   R 3  and R 4  may together form (CH 2 ) m  X 4  (CH 2 ) 1 , wherein m and 1 each represent 1, 2 or 3 while the sum of them is 3, 4 or 5; X 4  represents an oxygen atom; a sulfur atom; or NR 12  in which R 12  represents a hydrogen atom, a C 1  -C 4  alkyl group, or a phenyl group which is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group and a C 1  -C 4  alkoxy group; or   R 3  and R 4  may together form (CH 2 ) n  ZC(═Y), wherein n represents 2, 3 or 4; and Y represents an oxygen atom; a sulfur atom, or NR 7  in which R 7  represents a hydrogen atom, a cyano group, a nitro group, a C 1  -C 4  alkyl group, a C 1  -C 4  alkoxy group or CO 2  R 8  wherein R 8  represent a C 1  -C 4  alkyl group; and Z represents an oxygen atom; a sulfur atom; or NR 9  in which R 9  represents a hydrogen atom, a C 1  -C 6  alkyl group as defined above, a C 2  -C 6  alkenyl group as defined above, a C 2  -C 6  alkynyl group as defined above, a C 3  -C 6  cycloalkyl group as defined above, or a phenyl group as defined above.   
     
     
       2. A method for treating cardiac insufficiency comprising administering an effective dose of, as the active ingredient, at least one compound of the following formula (II), their optical isomers, their stereoisomers and their pharmacologically acceptable salts when they may form salts: ##STR77## wherein X 6  does not exist or represents an oxygen atom; X 5  represents an oxygen atom; a sulfur atom; or a nitrogen atom, said nitrogen atom is unsubstituted or substituted by a hydrogen atom or a C 1  -C 4  alkyl group; A 1  represents a hydrogen atom, a hydroxyl group, or OC(O)R 17  in which R 17  represents a C 1  -C 4  alkyl group;   B 1  represents a hydrogen atom;   R 13  and R 14  are the same or different from each other and represent a hydrogen atom or a C 1  -C 4  alkyl group;   R 15  and R 16  are the same or different from each other and represent: 1) a hydrogen atom;   2) a C 1  -C 6  alkyl group, said alkyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom; a carboxyl group; a C 2  -C 5  alkoxycarbonyl group; a hydroxyl group; a C 1  -C 4  alkoxy group; CH(OR) 2  in which R represents a C 1  -C 4  alkyl group; a phenyl group which is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group and a C 1  -C 4  alkoxy group; a formyl group; a cyano group and a nitro group;   3) a C 3  -C 6  cycloalkyl group, said cycloalkyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom; a carboxyl group; a C 2  -C 5  alkoxycarbonyl group; a hydroxyl group; a C 1  -C 4  alkoxy group; CH(OR) 2  in which R represents a C 1  -C 4  alkyl group; a phenyl group which is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group and a C 1  -C 4  alkoxy group; a formyl group; a cyano group and a nitro group;   4) a phenyl group which is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group and a C 1  -C 4  alkoxy group; or     R 15  and R 16  may together form a 1,4-butylene or 1,5-pentylene group, said butylene and said pentylene are unsubstituted or substituted by one or more substituents selected from a C 1  -C 4  alkyl group; a phenyl group which is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group and a C 1  -C 4  alkoxy group; a halogen atom, OR 21  in which R 21  represents a hydrogen atom, a C 1  -C 4  alkyl group, COR 22  wherein R 22  represents a C 1  -C 4  alkyl group; a nitro group; SO 3  H or PO 3  H 2  ; or   R 15  and R 16  may together form (CH 2 ) o  x 7  (CH 2 ) p  wherein o and p each is an integer of 1, 2 or 3 while the sum of them is 3, 4 or 5;   X 7  represents an oxygen atom; a sulfur atom; or NR 23 , wherein R 23  represents a hydrogen atom, a C 1  -C 4  alkyl group, or a phenyl group which is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group and a C 1  -C 4  alkoxy group; or   R 15  and R 16  may together form (CH 2 ) Q  Z 1  C(═Y 1 ), wherein Q represents an integer of 2, 3 or 4; and Y 1  represents an oxygen atom; a sulfur atom; or NR 19 , wherein R 19  represents a hydrogen atom, a cyano group, a nitro group, a C 1  -C 4  alkyl group or a C 1  -C 4  alkoxy group; and Z 1  represents an oxygen atom; a sulfur atom; or NR 20 , wherein R 20  represents a hydrogen atom, a C 1  -C 6  alkyl group as defined above; a C 3  -C 6  cycloalkyl group as defined above; or a phenyl group as defined above.   
     
     
       3. The method for treating cardiac insufficiency as claimed in claim 2, wherein R 15  in formula (II) represents a hydrogen atom; and R 16  represents C(═Y 2 )NHR 24 , wherein Y 2  represents an oxygen atom, a sulfur atom or N--CN; and R 24  represents a phenyl group, a benzyl group or a C 1  -C 8  alkyl group which may be branched. 
     
     
       4. The method for treating cardiac insufficiency as claimed in claim 2, wherein R 15  and R 16  in formula (II) together form (CH 2k  NHC(═Y 3 ), wherein k is an integer of 2, 3 or 4; and Y 3  represents an oxygen atom, a sulfur atom or N--CN. 
     
     
       5. The method for treating cardiac insufficiency as claimed in claim 2, in which R 15  and R 16  in formula (II) simultaneously represent C 1  -C 6  alkyl groups. 
     
     
       6. The method for treating cardiac insufficiency as claimed in claim 2, in which R 15  and R 16  in formula (II) together form (CH 2 ) 4  or (CH 2 ) 5 .